All currently available antidepressants can be classified in 3 classes:                1) monoamine oxidase inhibitors (MAOIs),        2) biogenic amine neurotransmitter [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] transporter reuptake blockers, and        3) modulators, especially blockers of one or more of the 5-HT and/or NE receptors.        
Since depression is associated with a relative deficiency of the biogenic amines, the use of 5-HT and/or NE-receptor blockers (i.e. 5-HT and or NE-antagonist's) has not proven very successful in the treatment of depression and anxiety and the preferred and currently most efficient treatments are based on the enhancement of 5-HT and/or NE neurotransmission by blocking their reuptake back from the synaptic cleft (Slattery, D. A. et al., “The evolution of antidepressant mechanisms”, fundamental and Clinical pharmacology, 2004, 18, 1-21; Schloss, P. et al, “new insights into the mechanism of antidepressant therapy”, Pharmacology and therapeutics, 2004, 102, 47-60).
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they generally are effective, well tolerated and have a favourable safety profile compared to the classic tricyclic antidepressants. Drugs claimed to be SSRIs are for example flouxetine, sertraline and paroxetine.
However, clinical studies on depression indicate that non-response to the known SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is the fact that there is generally a delay in therapeutic effect of the SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Furthermore, sexual dysfunction is generally a side effect common to SSRIs. Accordingly, there is a desire for the development of compounds capable of improving the treatment of depression and other serotonin related diseases.
A newer strategy has been the development of dual re-uptake inhibitors, e.g., the combined effect of 5-HT reuptake inhibition and NE (norepinephrine is also named noradrenaline, NA) reuptake inhibition on depression is explored in clinical studies of compounds such as Duloxetine (Wong, “Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate”, Expert Opinion on Investigational Drugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, 30 “Venlafaxine in depressed outpatients”, Psychopharmacology Bulletin, 1991, 27, 141-144). Compounds having such dual effect are also named SNRIs, “serotonin and noradrenaline reuptake inhibitors”, or NSRIs, “noradrenaline and serotonin reuptake inhibitors”.
Since treatment with the selective NE reuptake inhibitor reboxetine has been shown to stimulate 5-HT neurons and mediate the release of 5-HT in the brain (Svensson, T. et al, J. Neural. Transmission, 2004, 111, 127) there might be a synergistic advantage using SNRI's in the treatment of depression or anxiety.
The use of SNRI's has been shown in clinical studies to have a beneficial effect on pain (e.g. Fibromyalgia syndrome, overall pain, back pain, shoulder pain, headache, pain while awake and during daily activities) and especially pain associated with depression (Berk, M. Expert Rev. Neurotherapeutics 2003, 3, 47-451; Fishbain, D. A., et al. “Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review” Pain Medicine 2000 1:310-316).
SNRI's have also been shown in clinical studies to have a beneficial effect in attention deficit hyperactivity disorder (ADHD) (N. M. Mukaddes; Venlafaxine in attention deficit hyperactivity disorder, European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002, Page 421).
Furthermore, SNRI's have been shown to be effective for the treatment of stress urinary incontinence (Dmochowski R. R. et al. “Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence”, Journal of Urology 2003, 170:4, 1259-1263.)
Naranjo, C. et al. “The role of the brain reward system in depression” Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2001, 25, 781-823 discloses clinical and preclinical findings of links between lack of extra cellular dopamine in the mesocorticolimbic system and anhedonia, which is one of the main symptoms of depression.
Several studies suggest that serotonin and dopamine neurotransmission dysfunction contribute to the pathophysiology of several neuropsychiatric disorders, which include depression, schizophrenia and drug abuse (Fibiger, H. C., et al., “In Depression and Mania: from neurobiology to treatment” Raven Press, New York 1995, pp. 1-17; Roth, B. L., et al., J. Pharmacol. Exp. Ther. 1992, 260, pp. 1361-1365; Koob, G. F, et al., Trends Pharmacol. Sci. 1992, 13, pp. 177-184; Brown, A. S., et al., J. Neural. Trans. 1993, 91, pp. 75-109). Esposito, E., et al., “Serotonin-Dopamine Interaction as focus of Novel Antidepressant Drugs” Curr. Drug Targets 2006, 7, pp 177-185, suggests that drugs acting on the 5-HT system (e.g. SSRI's and 5-HT2C receptor antagonist) exert their antidepressant action by enhancing dopaminergic transmission in the mesolimbic system, and the use of such drugs, which influence the mesolimbic DA transmission might be important and useful in the search of new antidepressants for the treatment of depression.
Furthermore, Axford L. et al. describe the development of triple 5-HT, NE and DA re-uptake inhibitors for treatment of depression. (2003, Bioorganic & Medical Chemistry Letters, 13, 3277-3280: “Bicyclo[2.2.1.]heptanes as novel triple re-uptake inhibitors for the treatment of depression”). Wellbutrin (bupropion) which has DA re-uptake activity in vitro and in vivo, show antidepressant efficacy. Other combination studies have indicated that addition of some affininity at the DA uptake site may have some clinical benefit (Nelson, J. C. J. Clin. Psychiatry 1998, 59, 65; Masand, P. S. et al. Depression Anxiety 1998, 7, 89; Bodkin, J. A et al. J. Clin. Psychiatry 1997, 58, 137).
The combination of an SSRI and a norepinephrine and dopamine reuptake inhibitor, has been shown to have better efficacy in SSRI-non-responders (Lam R. W. et al. “Citalopram and Bupropion-SR: Combining Versus Switching in Patients With Treatment-Resistant Depression.” J. Clin. Psychiatry 2004, 65, 337-340).
There is clinical evidence suggesting that the combination of an SSRI and a norepinephrine and dopamine reuptake inhibitor induces less sexual dysfunction, than treatment with SSRI's alone (Kennedy S. H. et al. “Combining Bupropion SR With Venlafaxine, Paroxetine, or Duloxetine: A Preliminary Report on Pharmacokinetic, Therapeutic, and Sexual Dysfunction Effects” J. Clin. Psychiatry 2002, 63, 181-186).
The development of triple serotonin, norepinephrine and dopamine re-uptake inhibitors are currently the focus of many pharmaceutical companies, for their improved efficacy and reduced delay of action (Millan, M. J., et al. “Multi-target strategies for the improvement of depressive states: Conceptual Foundations And Neuronal Substrates, Drug Discovery And Therapeutic Application.” Pharmacology & Therapeutics. 110 (2006), 135-370).
The present invention provides novel indane compounds which are inhibitors of serotonin, norepinephrine and dopamine re-uptake. The compounds of the invention are therefore useful in the treatment of affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD), substance abuse, cognitive deficits and stress urinary incontinence.